Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
  • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
  • C07D513/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
  • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/06—Antiarrhythmics
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D498/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D515/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
  • C07D515/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
  • C07D515/04—Ortho-condensed systems

Definitions

• the present invention relates to benzopyran derivatives having the prolongation effect on the refractory period, which are used for the treatment of arrhythmia in mammals including human being.
• 4-acylaminobenzopyran derivatives exemplified by Cromakalim have been known (for example, Japanese Patent Laid-open No. Sho 58-67683 ). These 4-acylaminobenzopyran derivatives exemplified by Cromakalim are known to open ATP sensitive K + channel so as to be effective for the treatment of hypertension and asthma, but there has not been any mention as to the treatment of arrhythmia based on the prolongation effect on the refractory period.
• conventional anti-arrhythmic agents having the prolongation effect on the refractory period as a main mechanism such as Class I drugs of anti-arrhythmic agent classification according to Vaughan Williams, or d-sotalol or dofetilide belonging to Class III
• Class I drugs of anti-arrhythmic agent classification according to Vaughan Williams, or d-sotalol or dofetilide belonging to Class III have the therapeutic problems in inducing highly dangerous arrhythmia leading to the sudden death from such as torsades de pointes among others due to prolongation of action potential in ventricular muscle correlated to the prolongation effect on the refractory period.
• treating agents with less adverse effect have been highly desired.
• the inventors have investigated compounds having the prolongation effect on the refractory period selective for atrium muscle rather than for ventricular muscle in order to solve the problems, and consequently found that the compound of formula (I) or (II) has the prolongation effect on the refractory period selective for atrium muscle without any influence on the refractory period and action potential in ventricular muscle. Thus, the present invention has been accomplished.
• the present invention relates to the following aspects:
• the compound according to the present invention has a strong prolongation effect on the refractory period and it can be used as a drug for treating arrhythmia.
• n means normal, "i” means iso, “s” means secondary “t” means tertiary, “c” means cyclo, “o” means ortho, "m” means meta, “p” means para, "Ph” means phenyl, “Py” means pyridyl, "Bn” means benzyl, “Me” means methyl, “Et” means ethyl, “Pr” means propyl, "Bu” means butyl, “Pen” means pentyl, "Hex” means hexyl, "Ac” means acetyl, “Boc” means tertiary butoxycarbonyl and "MOM” means methoxymethyl in this specification.
• C 2-4 alkyl group examples are such as ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl and the like.
• C 1-6 alkyl group examples are such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, 1-pentyl, 2-pentyl, 3-pentyl, 1-pentyl, neopentyl, 2,2-dimethylpropyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-methyl-n-pentyl, 1,1,2,trimethyl-n-propyl, 1,2,2-trimethyl-n-propyl, 3,3-dimethyl-n-butyl and the like
• methyl, ethyl, n-propyl, i-propyl, n-butyl, n-pentyl and i-pentyl may be mentioned.
• C 3-8 cycloalkyl group are such as c-propyl, c-butyl, 1-methyl-c-propyl, 2-methyl-c-propyl, c-pentyl, 1-methyl-c-butyl, 2-methyl-c-butyl, 3-methyl-c-butyl, 1,2-dimethyl-c-propyl, 2,3-dimethyl-c-propyl, 1-ethyl-c-propyl, 2-ethyl-c-propyl, c-hexyl, c-heptyl, c-octyl, 1-methyl-c-hexyl, 2-methyl-c-hexyl, 3-methyl-c-hexyl, 1,2-dimethyl-c-hexyl, 1-methyl-c-pentyl, 2-methyl-c-pentyl, 3-methyl-c-pentyl, 1-ethyl-c-butyl, 2-ethyl-c-butyl, 3-e-
• c-pentyl and c-hexyl may be mentioned.
• C 3-8 cycloalkenyl group examples are such as 1-c-pentenyl, 2-c-pentenyl 3-c-pentenyl, 1-methyl-2-c-pentenyl, 1-methyl-3-c-pentenyl, 2-methyl-1-c-pentenyl, 2-methyl-2-c-pentenyl, 2-methyl-3-c-pentenyl, 2-methyl-4-c-pentenyl, 2-methyl-5-c-pentenyl, 2-methylene-c-pentyl, 3-methyl-1-c-pentenyl, 3-methyl-2-c-pentenyl, 3-methyl-3-c-pentenyl, 3-methyl-4-c-pentenyl, 3-methyl-5-c-pentenyl, 3-methylene-c-pentyl, 1-c-hexenyl, 2-c-hexenyl, 3-c-hexenyl 1-c-heptenyl, 2-c-heptenyl, 3-c-heptenyl, 4-o-heptenyl,
• 1-c-pentenyt 2-c-pentenyl, 3-c-pentenyl, 1-c-hexenyt 2-c-hexenyl and 3-c-hexenyl may be mentioned.
• halogen atom examples include fluorine atom, chlorine atom, bromine atom and iodine atom.
• fluorine atom, chlorine atom and bromine atom may be mentioned.
• C 6-14 aryl group examples are such as phenyl, o-biphenylyl, m-biphenylyl, p-biphenylyl, ⁇ -naphthyl, ⁇ -naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl, 9-phenanthryl and the like.
• phenyl, o-biphenylyl, m-biphenylyl, p-biphenylyl, ⁇ -naphthyl and ⁇ -naphthyl may be mentioned.
• C 2-9 heteroaryl group includes C 2-6 single-ring heterocyclic group with 5- to 7-member ring and C 5-9 fused double-ring heterocyclic group with member atom number of 8 to 10, which may contain 1 to 3 hetero atoms selected from the group consisting of oxygen atom, nitrogen atom and sulfur atom alone or in a combination.
• Examples of the C 2-6 single-ring heterocyclic group with 5- to 7-member ring are such as 2-thienyl group, 3-thienyl group, 2-furyl group, 3-furyl group, 2-pyranyl group, 3-pyranyl group, 4-pyranyl group, 1-pyrrolyl group, 2-pyrrolyl group, 3-pyrrolyl group, 1-imidazolyl group, 2-imidazolyl group, 4-imidazolyl group, 1-pyrazolyl group, 3-pyrazolyl group, 4-pyrazolyl group, 2-thiazolyl group, 4-thiazolyl group, 5-thiazoyl group, 3-isothiazolyl group, 4-isothiazolyl group; 5-isothiazolyl group, 2-oxazolyl group, 4-oxazolyl group, 5-oxazolyl group, 3-isoxazolyl group, 4-isoxazolyl group, 5-isoxazolyl group, 2-pyridyl group, 3-pyridyl group, 4-pyridy
• Examples of the C 5-9 fused double-ring heterocyclic group with member atom number of 8 to 10 are 2-benzofuranyl group, 3-benzofuranyl group, 4-benzofuranyl group, 5-benzofuranyl group, 6-benzofuranyl group, 7-benzofuranyl group, 1-isobenzofuranyl group, 4-isobenzofuranyl group, 5-isobenzofuranyl group, 2-benzothienyl group, 3-benzothienyl group, 4-benzothienyl group, 5-benzothienyl group, 6-benzothienyl group, 7-benzothienyl group, 1-isobenzothienyl group, 4-isobenzothienyl group, 5-isobenzothienyl group, 2-chromenyl group, 3-chromenyl group, 4-chromenyl group, 5-chromenyl group, 6-chromenyl group, 7-chromenyl group, 8-chromenyl group, 1-indolizinyl group, 2-in
• 2-pyridyl group, 3-pyridyl group and 4-pyridyl group may be mentioned.
• the preferable compounds used in the present invention include the followings:
• R 6 is benzene ring.
• the compound according to the present invention has asymmetric carbon atoms at 3-position and 4-position, thus optical isomers thereof based on the asymmetric carbon atoms are present, and optical active substances can be also used in the application of the present invention, like racemic modifications. Further, cis- and trans-isomer based on configuration at 3-position and 4-position may be included, but trans-isomer is preferred.
• the pharmaceutically acceptable salts thereof can also be used as active ingredients.
• Examples of pharmaceutically acceptable salt are such as hydrochlorides, hydrobromides, sulfates, methanesulfonates, acetates, benzoates, tartrates, phosphates, lactates, maleates, fumarates, malates, gluconates, salicylates and the like.
• hydrochlorides, maleates and methanesulfonates may be mentioned.
• the compound of formula (I-a) or (II-a) that is the compound of form ula (I) or (II) wherein R 4 is hydrogen atom and R 3 is hydroxy group can be obtained by reacting the compound of formula (1) or (2) with the compound of formula (3) in an inert solvent as shown in the scheme below.
• the reaction temperature is generally from -80°C to the reflux temperature of the reaction solvent, preferably from -10°C to 100°C.
• the molar ratio of the reaction materials is within the range of 0.5-4.0, preferably 1.0-2.0, for compound (3)/compound (1) or (2).
• Acid catalysts may be used in the reaction.
• the acid catalysts used include inorganic acids exemplified by hydrochloric acid and sulfuric acid, Lewis acids exemplified by aluminum chloride, titanium tetrachloride, boron trifluoride diethylether complex, perchloric acid, lithium perchlorate, lithium bromide and ytterbium trifluoromethanesulfonate.
• Preferable acid catalysts are lithium bromide and lithium perchlorate.
• optically active compounds in the compounds of formula (I) or (II) is accomplished by use of a method for optical resolution of racemate (Japanese Patent Laid-open No. Hei 3-141286 , US Patent No. 5097037 and EP Patent No. 409165 ).
• the compound of formula (1-a) or (2-a) that is the compound of formula (I) or (II) wherein A is the group of formula (5), R 4 is hydrogen atom and R 3 is hydroxy group can be obtained from the compound of formula (6) or (7) according to known methods (methods described in J. M. Evans et al., J. Med. Chem. 1984, 27, 1127 ; J. Med. Chem. 1986, 29, 2194 ; J. T. North et al., J. Org. Chem. 1995, 60, 3397 ; as well as Japanese Patent Laid-open Nos. Sho 56-57785 , Sho 56-57786 , Sho 58-188880 , Hei 2-141 , Hei 10-87650 and Hei 11-209366 and the like).
• the compound of formula (6) or (7) can be obtained by reacting compound (8) with compound (9) (see, Y. Tsuji et al., J. Org. Chem., 1987, 52, 1673 ).
• the reaction temperature is generally from -80°C to the reflux temperature of the reaction solvent, preferably from -10°C to 200°C.
• the molar ratio of the reaction materials is within the range of 0.1-4.0, preferably 0.5-2.0, for compound (8)/compound (9).
• Transition metal catalysts and ligands may be used in the reaction.
• the transition metal catalysts used include ruthenium chloride, dichlorotris(triphenylphosphine)ruthenium, dibromotris(triphenylphosphine)ruthenium, dihydridetetrakis(triphenylphosphine)ruthenium, ( ⁇ 4-cyclooctadiene)( ⁇ 6-cyclooctatriene)ruthenium, dichlorotricarbonyl ruthenium dimer, dodecacarbonyl triruthenuim, ( ⁇ 5-pentamethylcyclopentadienyl)chloro( ⁇ 4-cyclooctatriene)ruthenium, palladium acetate, palladium chloride, dichlorobis(triphenylphosphine)palladium, tetrakistriphenylphosphine palladium, bis(dibenrylideneacetone)palladium, rhodium chloride, chlorotris(triphenylphosphine
• ruthenium chloride may be mentioned.
• the ligands include monodentate phosphine ligands exemplified by trimethylphosphine, triethylphosphine, tri- n -propylphosphine, tri- i -propylphosphine, tri-n-butylphosphine, tri- t -butylphosphine, tricyclohexylphosphine, triphenylphosphine and tri(o-tolyl)phosphine, bidentate phosphine ligands exemplified by 1,2-bisdiphenylphosphinoethane, 1,3-bisdiphenylphosphinopropane, 1,4-bisdiphenylphosphinobutane and1,2-diethylphosphinoethane, phosphite ligands exemplified by triethylphosphite, tributylphosphite, triphenylphosphit
• triphenylphosphine tri- n -butylphosphine and tri- t -butylphosphine.
• the compound of formula (6) or (7) can be also obtained by reacting compound (8) with compound (10) in the presence of an acid catalyst (see, Y Kitahara et al., Tetrahedron Lett., 1997, 53, 6001 , Z. Song et al., J. Heterocyclic Chem., 1993, 30, 17 ).
• Sulfoxide type solvents exemplified by dimethylsulfoxide; amide type solvents exemplified by dimethylformamide and dimethylacetamide; ether type solvents exemplified by diethyl ether, dimethoxyethane, tetrahydrofuran, dioxane and diethylene glycol dimethyl ether; halogen type solvents exemplified by dichloromethane, chloroform and dichloroethane; nitrile type solvents exemplified by acetonitrile and propionitrile; aromatic hydrocarbon type solvents exemplified by benzene and toluene; hydrocarbon type solvents exemplified by hexane and heptane; ester type solvents exemplified by ethyl acetate; alcohol type solvents exemplified by methanol, ethanol, 1-propanol, 2-propanol and ethylene glycol; organic acid type solvents exemp
• the acid catalysts used include inorganic acids exemplified by hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid, organic sulfonic acids exemplified by methane sulfonic acid and paratoluene sulfonic acid, Lewis acids exemplified by aluminum chloride, titanium tetrachloride, boron trifluoride diethylether complex, perchloric acid, zinc chloride, zinc bromide, zinc iodide, iron(III) chloride, iron(II) chloride. copper(I) chloride and copper(II) chloride.
• hydrochloric acid and zinc chloride may be mentioned.
• the reaction temperature is generally from -80°C to the reflux temperature of the reaction solvent, preferably from -10°C to 200°C.
• the molar ratio of the reaction materials is within the range of 1-10, preferably 1-3, for compound (10)/compound (8).
• syntheses of optically active compounds in the compounds of of formula (1) or (2) can be attained by utilizing asymmetric synthetic methods (PCT Japanese Translation Patent Publication No. Hei 5-507645 , Japanese Patent Laid-open Nos. Hel 5-301878 and Hei 7-285983 , European Patent Laid-open No. 535377 and U.S. Patent No. 5420314 ).
• the compound of formula (I-a) or (II-a) that is the compound of formula (I) or (II) wherein R 4 is hydrogen atom and R 3 is hydroxy group can be obtained by subjecting the compound of formula (11) or (12) and the compound of formula (13) to reductive amination reaction in an inert solvent as shown in the scheme below.
• the compound of formula (I-c) or (II-c) that is the compound of formula (I) or (II) wherein R 4 is hydrogen atom, R 3 is hydroxy group and A is the group of formula (15) can be also obtained by reacting the compound of formula (16) or (17) with the compound of formula (18) in an inert solvent as shown in the scheme below.
• the reaction temperature is generally from -80°C to the reflux temperature of the reaction solvent, preferably from -10°C to 50°C.
• the molar ratio of the reaction materials is within the range of 0.5-4.0, preferably 0.8-2.0, for compound (18)/compound (16) or (17).
• the compound of formula (I-d) or (II-d) that is the compound of formula (I) or (II) wherein R 4 is hydrogen atom, R 3 is hydroxy group and A is the group of formula (19) can be also obtained by subjecting the compound of formula (20) or (21) to reduction reaction in an inert solvent as shown in the scheme below.
• the compound of formula (I-e) or (II-e) that is the compound of formula (I) or (II) wherein R 4 is hydrogen atom, R 3 is hydroxy group and A is the group of formula (22) (X is SO 2 or CO, and Y is S or O) can be also obtained by subjecting the compound of formula (23) or (24) to ring-closure reaction in an inert solvent under basic conditions as shown in the scheme below.
• the inventors of the present invention found that the compound of formula (I) or (II) has a strong prolongation effect on the refractory period.
• the prolongation effect on the refractory period is one of mechanisms of anti-arrhythmic action and is an important indicator that can be taken in judging the effectiveness in clinical arrhythmia.
• Conventional anti-arrhythmic agents having the prolongation effect on the refractory period as the main mechanism have been the therapeutic problems in inducing highly dangerous arrhythmia leading to the sudden death from such as torsades de pointes among others due to prolongation of action potential in ventricular muscle correlated to the prolongation effect on the refractory period, and thus becoming the therapeutic problem in arrhythmia mainly of atrial muscle (such as supraventricular tachycardia, atrial flutter, atrial fibrillation and the like).
• the inventors of the present invention carried out the investigation of compounds having the prolongation effect on the refractory period selective for atrium muscle than for ventricular muscle, and found that the compound of formula (I) or (II) has a prolongation effect on the refractory period selective for atrium muscle without any influence on the refractory period and action potential in ventricular muscle.
• the difference between the findings by the inventors and the prior art is in providing the prolongation effect on the refractory period selective for atrium muscle to these compound group, which may be shown by the facts that there is no influence on the action potential duration period of isolated ventricular muscle and there is no influence on QT in the electrocardiogram of anesthetized animal.
• the compounds of the present invention show no inducing action of arrhythmia in ventricular muscle, thus they can contribute to much safer use in arrhythmia mainly of atrial muscle in comparison with the prior art.
• the present technical knowledge is beneficial for therapeutic or preventive uses as anti-atrial fibrillation agents, anti-atrial flutter agents and anti-atrial tachycardia agents relating to paroxysmal, chronic, preoperative, intraoperative or postoperative atrial arrhythmia, prevention in the progression leading to embolus due to arrhythmia of artial nature, prevention in the progression leading to ventricular arrhythmia or tachycardia from atrial arrhythmia or tachycardia, and averting the life threatening prognosis due to preventive action on atrial arrhythmia or tachycardia leading to ventricular arrhythmia or tachycardia.
• the present invention provides a pharmaceutical composition or a veterinary pharmaceutical composition containing a compound of formula (I) or (II) in an effective amount for these treatments.
• parenteral administration forms such as injections (subcutaneous, intravenous, intramuscular and intraperitoneal injections), ointments, suppositories, aerosols and the like, and oral administration forms such as tablets, capsules, granules, pills, syrups, solutions, emulsions, suspensions and the like can be mentioned.
• the pharmaceutical or veterinary pharmaceutical composition described above contains the compound according to the present invention in an amount of about 0.01-99.5%, preferably about 0.1-30%, based on the total weight of the composition.
• composition containing the compound in addition to the compound according to the present invention or the composition containing the compound, other pharmaceutically or veterinary pharmaceutically active compounds may be contained.
• compositions may contain the plurality of compounds according to the present invention.
• An amount of the compound according to the present invention to be used in clinical administration may vary depending on age, weight and sensitivity of the patient, symptomatic condition and the like, but an effective amount in clinical administration is generally about 0.003-1.5 g, preferably 0.01-0.6 g, per day for adult. If necessary, however, the amount outside of the aforementioned range may be used.
• the compound according to the present invention is formulated for administration by conventional pharmaceutical means.
• tablets, capsules, granules and pills for oral administration are prepared by using excipients such as sucrose, lactose, glucose, starch and mannitol; binders such as hydroxypropyl cellulose, syrup, gum arabic, gelatin, sorbitol, tragacanth, methyl cellulose and polyvinyl pyrrolidone; disintegrators such as starch, carboxymethyl cellulose or its calcium salt, microcrystalline cellulose and polyethylene glycol; lubricants such as talc, magnesium or calcium stearate, and silica; lubricaing agents such as sodium laurate and glycerol and the like.
• excipients such as sucrose, lactose, glucose, starch and mannitol
• binders such as hydroxypropyl cellulose, syrup, gum arabic, gelatin, sorbitol, tragacanth, methyl cellulose and polyvinyl pyrrolidone
• disintegrators such as starch,
• solvents for the active components such as water, ethyl alcohol, isopropyl alcohol, propylene glycol, 1,3-butylene glycol and polyethylene glycol; surfactants such as sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene ether of hydrogenated castor oil and lecithin; suspending agents such as carboxymethyl sodium salt, cellulose derivatives such as methyl cellulose or the like, and natural rubbers such as gum arabic, tragacanth or the like; and preserves such as p-hydroxybenzoic acid esters, benzalkonium chloride, sorbic acid salts and the like.
• solvents for the active components such as water, ethyl alcohol, isopropyl alcohol, propylene glycol, 1,3-butylene glycol and polyethylene glycol
• surfactants such as sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene
• ointments that are transdermally adsorptive pharmaceutics for example, white vaseline, liquid paraffin, higher alcohols, Macrogol ointments, hydrophilic ointments, aqueous gel-type bases and the like are used.
• Suppositories are prepared by using, for example, cocoa fats, polyethylene glycol, lanolin, fatty acid triglyceride, coconut oil, polysorbate and the like.
• Ph,Ph salen manganese complex (XX) and Cyc,Ph salen manganese complex (XY) mean optically active compounds of formula below which were synthesized according to the method similar to one described in Japanese Patent Laid-open No. Hei 7-285983 .
• the resulting mixture was added dropwise to a mixed solution of 6-hydroxyquinoline (2.43 g, 16.7 mmol), copper (I) chloride (8.3 mg, 0.0835 mmol), acetonitrile (15.5 mL) and 1,8-diazabicyclo-[5.4.0]-7-undecene (4.25 mL, 28.4 mmol) at 0°C, and stirred at 0°C for 3 hours.
• the resulting solution was acidified with 1 mol/L HCl and extracted with ethyl acetate, and the resulting aqueous phase was neutralized with aqueous sodium hydrogencarbonate solution, extracted with ethyl acetate, and dried over anhydrous magnesium sulfate.
• aqueous sodium hypochlorite solution (25.6 g, 1.513 mol/kg, 38.8 mmol) was added, and the resulting mixture was stirred in water bath for 1 hour.
• aqueous sodium hydrogencarbonate solution was added to the reaction solution, and it was extracted with ethyl acetate and the resulting organic phase was washed with aqueous sodium hydrogencarbonate solution and then with aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by column chromatography (ethyl acetate). Further, after distilling off the solvent, ethyl acetate (2 mL) was added and a solution of maleic acid (376 mg, 3.23 mmol) in ethyl acetate (8mL) was added dropwise.
• Synthesis Examples 20-49 were carried out similarly to the process of Synthesis Example 19.
• This compound was synthesized by using the enantiomer of Ph,Ph salen manganese complex (XX) (hereinafter, referred to as ent-Ph,Ph salen manganese complex).
• Aqueous sodium hypochlorite solution (1.0 g, 1.513 mol/kg, 1.54 mmol) was added dropwise, and the resulting mixture was further stirred at room temperature for 30 minutes. Upon the completion of the reaction, aqueous sodium thiosulfate solution was added to the reaction solution, the resulting solution was filtered through celite and extracted. The organic phase was washed with aqueous sodium hydrogencarbonate solution and then with aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate.
• 1,2-epoxypentane (71 ⁇ L, 0.682 mmol) was added to a solution of (3 R *,4 S *)-4-amino-7-chloro-2,2,9-trimethyl-3,4-dihydro-2 H -pyrano[2,3-g]quinolin-3-ol (100 mg, 0.343 mmol) and lithium perchlorate (36 mg, 0.343 mmol) in dioxane (0.50 mL) at room temperature, and the resulting mixture was stirred at 70°C for 25 hour.
• Synthesis Example 60 was carried out similarly to the process of Synthesis Example 59.
• Synthesis Example 61 was carried out similarly to the process of Synthesis Example 59.
• Synthesis Example 62 was carried out similarly to the process of Synthesis Example 59.
• Synthesis Example 63 was carried out similarly to the process of Synthesis Example 59.
• Synthesis Example 64 was carried out similarly to the process of Synthesis Example 59.
• Synthesis Example 66 was carried out similarly to the process of Synthesis Example 59. (Yield: 33%, law polar component) White amorphous product 1 H-NMR (CDCl 3 ) ⁇ : 1.27 (s, 3H), 1.57 (s, 3H), 1.66 (br s.
• Synthesis Example 68 was carried out sim ilarly to the process of Synthesis Example 59.
• N -bromosuccinimide (1.21 g, 6.78 mmol) was added at room temperature, and the resulting mixture was stirred for 3 hours.
• saturated aqueous ammonium chloride solution was added thereto, the resulting solution was extracted with ethyl acetate, washed with saturated aqueous sodium hydrogencarbonate solution and then with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated.
• This compound was synthesized according to the process of Synthesis Example 59.
• the resulting organic phase was washed with aqueous sodium hydrogencarbonate solution and then with aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate.
• acetic anhydride 46 mL was added to the residue at room temperature, and the resulting mixture was stirred at 150°C for 1 hour.
• acetic anhydride was distilled off, the residue was neutralized with aqueous sodium carbonate solution, extracted with chloroform, and the resulting organic phase was washed with aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate.
• the resulting organic phase was washed with aqueous sodium hydrogencarbonate solution and then with aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate.
• acetic anhydride 46 mL was added to the residue at room temperature, and th e resulting mixture was stirred at 150°C for 1 hour.
• acetic anhydride was distilled off, the residue was neutralized with aqueous sodium carbonate solution, extracted with chloroform, and the resulting organic phase was washed with aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate.
• This compound was synthesized by using the compound of Synthesis Example 23 similarly to the process of Synthesis Example 86.
• This compound was synthesized by using the compound of Synthesis Example 52 similarly to the process of Synthesis Example 86.
• a compound according to the invention 10g Lactose 260g Microcrystalline cellulose 600g Corn starch 350g Hydroxypropyl cellulose 100g CMC-Ca 150g Magnesium stearate 30g Total weight 1,500g
• the aforementioned ingredients were mixed by a conventional method and then 10,000 sugar-coated tablets each containing 1 mg of the active ingredient per tablet were prepared.
• a compound according to the invention 10g Lactose 440g Microcrystalline cellulose 1,000g Magnesium stearate 50g Total weight 1,500g
• the aforementioned ingredients were mixed by a conventional method and then filled into gelatin capsules to prepare 10,000 capsules each containing 1 mg of the active ingredient per capsule.
• a compound according to the invention 10g PEG 400 479g Saturated fatty acid triglyceride 1,500g Peppermint oil 1g Polysorbate 80 10g Total weight 2,000g
• the aforementioned ingredients were mixed by a conventional method and then filled into No. 3 soft gelatin capsules to prepare 10,000 soft capsules each containing 1 mg of the active ingredient per capsule.
• a compound according to the invention 1.0g Liquid paraffin 10.0g Cetanol 20.0g White vaseline 68.4g Ethylparaben 0.1g 1-menthol 0.5g Total weight 100.0g
• a compound according to the invention 1g Witepsol H15* 478g Witepsol W35* 520g Polysorbate 80 1g Total weight 1,000g (* trade name for triglyceride type compounds)
• the aforementioned ingredients were melt-mixed by a conventional method, poured into suppository containers and cooled to solidify, and 1,000 suppositories (1g) each containing 1 mg of the active ingredient per suppository were prepared.
• a compound according to the invention 1mg Distilled water for injection 5mL
• ECG electrocardiogram
• Atrial and ventricular effective refractory periods were determined by S1-S2 extrastimulus technique at basic cycle length of 300 msec during bilateral vagal nerve stimulation, using programmable electric stimulator.
• a train of 10 basic stimuli(S1) was followed by a premature extrastimulus (S2) at 2 times diastolic threshold.
• S1-S2 interval was successively decreased by 2 msec, and the effective refractory period was defined as the point at which S2 failed to produced a propagated response.
• the atrial and ventricular effective refractory periods were determined before drug administration, then respective compound was administrated intravenously at the dose of 0.3 mg/kg or 0.6 mg/kg, and the atrial and ventricular effective refractory periods were determined from 5 minutes after the administration.
• the compounds of the present invention exhibited the prolongation effect on the effective refractory period selective for atrium as shown in Table below.
• Table Synthesis Example No. Dose (mg/kg) (mg/kg) Atrial Refractory Period (msec) 2 0.6 21 4 0.6 30 6 0.6 20 7 0.6 25 8 0.6 23 14 0.3 27 18 0.3 27 19 0.3 26 23 0.3 22 24 0.3 23 25 0.3 27 26 0.3 24 27 0.3 32 41 0.3 21 47 0.3 24 48 0.3 23 52 0.3 28 53 0.3 30 58 0.3 28 59 0.3 22 60 0.3 22 61 0.3 20 63 0.3 23 69 0.3 37 71 0.3 31 73 0.3 31 74 0.3 25 77 0.3 25
• the compounds according to the present invention exhibit the prolongation effect on the effective refractory period selective for atrium, thus can be used as an anti-atrial fibrillation agents and an supraventricular antiarrhythmic agent, and are useful as pharmaceuticals. Further, since the compounds according to the present invention have small influence on ventricle, they can contribute to safe treatments of aforementioned arrhythmic conditions.

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